Abstract Acute kidney injury (AKI) is a common condition and is associated with both short- and long-term adverse outcomes in those who develop it. Translational research studies of actual human kidney tissue during an AKI event can lead to discovery of novel AKI pathways and therapeutic targets. In response to the RFA-DK-16-026, also known as the Kidney Precision Medicine Program, our proposal aims to safely and ethically enroll a diverse group of participants with AKI. Our proposal aims to balance the need for obtaining kidney tissue from a diverse AKI population with the risks of obtaining this tissue. Kidney biopsies carry a small but significant risk of bleeding which may be somewhat increased in the setting of AKI. In the AKI Matched Phenotype Linked Evaluation with Tissue (AMPLE-Tissue) Study, we propose that the optimal way to obtain tissue in AKI patients would be through a combination of approaches. First, we will obtain extra tissue at the time of clinically indicated kidney biopsies, since prior data suggests that this approach does not add additional bleeding risk. We will carefully select participants who are at lower risk of bleeding. Over the last two years, we have enrolled over 200 participants in a research study and collected kidney biopsies from them. Over 70% of these participants said that they would be willing to donate extra tissue for research. Second, to encompass the whole AKI spectrum from its mildest to severest forms, we will also biopsy kidneys in deceased donors. The causes of AKI in deceased donors are similar to those experienced by critically ill AKI patients. Obtaining biopsies in this setting is low-risk; we have successfully enrolled over 900 deceased patients who received kidney biopsies in an ongoing NIH-funded project. Third, we will obtain research-only biopsies in specially-selected settings of hepatorenal syndrome and obstructive kidney disease when bleeding risk is low. In the UG3 phase, our aim is to obtain biopsies from 90-100 participants over two years and closely monitor patient safety. We will establish a community advisory board of AKI patients in addition to a data and safety monitoring board for the study. We will share data within the consortium after removal of patient identifiers. We will also establish linkages with various electronic medical record system as well as administrative databases to streamline follow-up. In the UH3 phase, we will expand our study to other sites and settings based on the biopsy quality and safety data from UG3 phase and enroll 375 participants over three years. We will also conduct longitudinal follow-up on all participants using various mechanisms which were effective for us in the past.